Twenty-four patients with a variety of solid tumors entered a Phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single oral dose of 10-60 mg/m2 repeated every 3-4 weeks. Leukopenia was the dose-limiting toxicity. Other toxic effects included mild to moderate nausea and vomiting. Sixty mg/m2 was found to be the maximum tolerated dose in patients with fair tolerance to chemotherapy and normal liver function. Similar hematologic toxicity was reported in patients with very extensive prior chemotherapy or diffuse bone and/or liver metastases receiving 50 mg/m2. However, the wide range of the WBC nadirs reported with the same dose in 'good risk' cases, suggest that 40 mg/m2, increased up to 50 mg/m2 in the absence of significant myelotoxicity, could be more safely proposed as starting dose for Phase II trials. Pharmacokinetic studies were performed in five patients given a single dose of 40-60 mg/m2. IMI-30 (NSC 256439) appears to be rapidly absorbed and rapidly eliminated from plasma by means of a rapid and extensive biotransformation to 13-OH-idarubicin. The 13-dihydroderivative was present at higher and more prolonged levels than the parent compound, with an elimination half-life of about 40 hours.

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Carboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200-550 mg/m2 every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m2 Carboplatin, the median platelet nadir was 65 000/mm3. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50-155) ml/min and dropped to a median lowest creatinine clearance of 69 (23-171) ml/min on day four (p less than 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42-155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m2 every five weeks. A starting dose of 450 mg/m2 seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200-500 mg/m2 induced renal and severe hematological toxicity.

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Twenty-six patients with various solid tumors entered a Phase I trial with 4'-Deoxydoxorubicin (Esorubicin, IMI-58), a new doxorubicin analogue. The drug was administered weekly i.v. for 3-4 weeks. Leukopenia proved to be dose limiting. The maximum tolerated dose (MTD) was reached at 20 mg/m2 weekly for 3 weeks. For Phase II trials, a weekly dose of 15 and 17.5 mg/m2 can be proposed for poor and good risk patients respectively. Non-hematologic toxicity was minimal. Phase II trials with this new anthracycline are warranted.